This program project proposes two major approaches to the improvement of cancer chemotherapy. 1) By identifying critical biochemical, pharmacological and pharmacokinetic parameters of response to chemotherapy in patients with leukemias, lymphomas and solid tumors to be able to move towards the prediction, prior to therapy, of response to chemotherapy with specific agents and thus, of modifying chemotherapeutic approaches to patients with cancer. Such investigations will include an intensive analysis of the determinants of the activity of interferon and other biological response modifiers and determinants of antimetabolites and alkylating agents in an attempt to assess the basis for sensitivity and the rate of resistance to chemotherapy. The second major thrust will be an attempt to develop new treatments through the introduction and intensive study of new cancer chemotherapeutic agents and new combinations based on the knowledge of biochemical pathways and ways in which modulation by the co-administration of other compounds can be achieved. Antimetabolites will be examined for their uptake into cells, their activation and the interaction of the activated metabolites with target macromolecules. Other agents will be investigated in terms of their specific interactions with DNA and the relationship of specific DNA damage to cell death. Efforts will be directed towards determining the extent to which pharmacokinetic information can be used to modify drug treatment both with new and with established agents. Multiple correlates of response to chemotherapy in patients will be integrated and focused by intensive biomathematical support.